The replacement or filling of a biological tissue or the increase of tissue volume can be necessary or desirable in many therapeutic and cosmetic applications. One way to achieve this is the introduction of viscoelastic products based on permanent or biodegradable materials into the biological tissue.
With regard to therapeutic applications, the viscoelastic products can be used for increasing the volume of certain tissues, for example of the sphincter, the urethra or the vocal cords. In case of cosmetic applications, potential applications include filling of wrinkles, masking scars or augmenting the volume of the lips. The injection of viscoelastic products is a simple non-invasive method with fewer risks than aesthetic surgery.
The use of viscoelastic products based on permanent materials offers the advantage of a long residence time in the tissue, but has major drawbacks. For example, the injection of silicone is associated with undesirable long-term effects characterized by the appearance of nodules and ulcers of the skin. Further, the injection of particles in solution or in a biopolymer matrix entails the risk of unwanted inflammatory reactions, and the migration of synthetic fragments may even lead to the appearance of granulomas.
Therefore, viscoelastic products based on crosslinked biodegradable biopolymers in the form of gels are increasingly used in therapeutic treatments and in the dermo-cosmetic field. The biodegradable polymers used in these gels are typically naturally occurring polymers that can be resorbed over time in the tissue where they have been injected. A large majority of the commercial gel products, in particular of dermal fillers, employ crosslinked hyaluronic acid (HA) as a preferred biodegradable polymer. Different crosslinking agents such as DVS (divinyl sulfone), DEO (diepoxyoctane) and BDDE (1,4-butanediol diglycidyl ether) can be used.
Biodegradable biopolymer gels are commonly classified in two different types, the “single-phase” (or “monophasic”) gels and the “two-phase” (or “biphasic”) gels. The biphasic gels comprise a material that consists of one or more crosslinked biopolymers (e.g., sodium hyaluronate) dispersed within a fluid phase or in a non-crosslinked biopolymer-based solution (see, e.g., EP 0 466 300 B1). The crosslinked biopolymer material degrades slowly by surface degradation, whereas the non-crosslinked biopolymer (e.g., sodium hyaluronate) degrades very quickly. As a result, when an increase in tissue volume is desired, numerous after-treatments are necessary after the first injection, which reduces the user's quality of life. Examples of commercially available biphasic, biodegradable gels include, among others, the dermal fillers Hylaform®, Restylane®, and Perlane®.
The monophasic gels are also based on one or more crosslinked biodegradable biopolymers (e.g., sodium hyaluronate), but comprise only a single phase, meaning it is a gel with no visible particles. In view of the crosslinked nature, these gels undergo slow surface degradation. Such monophasic viscoelastic gels have been described, for example, in WO 2008/068297 A1, U.S. Pat. No. 8,450,475 B2, U.S. Pat. No. 8,455,465 B2, U.S. Pat. No. 7,741,476 B2, and U.S. Pat. No. 8,052,990 B2. Commercial monophasic HA gels include, among others, Juvederm®, Teosyal®, Glytone®, and the monophasic, double-crosslinked (polydensified) HA gels marketed under the brand names Belotero®, Esthélis®, Fortélis® Extra, and Modélis® Shape.
An improved persistence, i.e. a longer residence time in the human body, of fillers is thought to be beneficial due to the expected reduction in the number and frequency of treatments required to obtain a satisfactory result. The cross-linking significantly improves the persistence. However, the injection of a highly crosslinked polymer is more difficult which is an undesirable characteristic. In addition, upon injection of the gel, the non-crosslinked sites of the polymer become more prone to biochemical and enzymatic attacks, which promotes degradation of the gel.
Therefore, additional attempts have been made to further increase the persistence of biopolymer-based fillers. For example, it was proposed to incorporate particles made from crosslinked HA or (meth)acrylic acid into a crosslinked HA polymer matrix (see, e.g., WO 00/01428 A1 and US 2010/0028435 A1). This approach, however, is associated with the risk of unwanted inflammatory reactions and even granulomas. In addition, WO 2013/149161 A1 discloses the production of high molecular weight heparosan, a polymer that is similar to HA but is more resistant against degradation, and proposes its use as a biomaterial composition for, among others, tissue augmentation.